Disease, injury and surgery can result in localized tissue damage and morbidity. For example, the principal treatment for occlusive vascular diseases is angioplasty, a procedure in which a balloon is inserted into the vessel and then inflated to dilate the area of narrowing. During inflation, the balloon can damage the vessel wall. It appears that as a result of this damage, in 30 to 50% of cases, the initial increase in lumen dimensions is followed by a localized re-narrowing (restenosis) of the vessel over a time of three to six months. Thus, restenosis can result in the dangerous and localized renarrowing of a patient's vessel at the site of the recent angioplasty. Like many other localized diseases, restenosis is complex and at present there is no clinically effective treatment for this disease. Gibbons et al., Molecular Therapies for Vascular Diseases, Science vol. 272, pages 617-780 (May 1996).
Restenosis, like many other localized injuries and diseases, has responded poorly to pharmacological therapies and agents. Numerous pharmacological agents have been clinically tested, and none have demonstrated an unequivocal reduction in the incidence of restenosis. However, the failure of these pharmacological therapies may arise from the systemic intolerance of the doses required to achieve local beneficial effects or in the difficulty of providing controlled administration of proper dosages over time. Accordingly, one possible reason for the failure of these therapies is that submaximal doses of pharmacological agents are being administered to avoid the serious side-effects that might result from systemic administration of the proper dosage.
To address this problem, various researchers have proposed methods for site-specific delivery of pharmacologic and molecular therapies. These methods include the direct deposition of therapeutic agents into the arterial wall through an intravascular delivery system, systemic administration of therapeutic agents that have a specific affinity for the injured or diseased tissue, and systemic administration of inactive agents followed by local activation.
At present, systems exist that attempt to achieve localized delivery of therapeutic agents. These systems include dual balloon delivery systems that have proximal and distal balloons that are simultaneously inflated to isolate a treatment space within an arterial lumen. A catheter extends between the two balloons and includes a port that can admit within the treatment space between the balloons an aqueous medium, typically one containing a therapeutic agent. Pressure can be applied to the medium to create conditions conducive to intramural infusion. Other balloon-based localized delivery systems include porous balloon systems, hydrogel-coated balloons and porous balloons that have an interior metallic stent. Other systems include locally placed drug-loaded coated metallic stents and drug-filled polymer stents. Wilensky et al., Methods and Devices for Local Drug Delivery in Coronary and Peripheral Arteries, Trend Cardiovasc Med, vol. 3 (1993).
Although these systems can provide working devices for local drug delivery, the efficacy of these devices turns on, and is limited by, a number of factors including the rate of fluid flux through the vascular wall, the residence time of the deposited agent and the local conditions and vasculature of the deposition site. Essentially, the success of these systems is limited by the amount of time that a delivered drug will stay resident locally before being carried downstream by circulating blood. Further, to the extent that these systems allow the therapeutic agent to be carried away, these systems run the risk of applying a therapeutic agent to areas of the patient's vasculature where such agents may not be beneficial. Additionally, these existing systems are limited by the amount of drug that can be delivered to the diseased site. Moreover, drug filled polymer stents have structural problems that argue against their use.
It would be advantageous to develop other methods of treatment for patients having localized cardiovascular conditions and in particular to develop methods of treatment that reduce adverse side effects and have heightened efficacy.